Aminothiazole derivatives

ABSTRACT

Compounds of formula I 
                         
as well as pharmaceutically acceptable salts and esters thereof, wherein R 1  to R 4  have the significance given in the specification, and the compounds, salts and esters can be used for the treatment of obesity.

BACKGROUND OF THE INVENTION

Neuropeptide Y is a 36 amino acid peptide that is widely distributed inthe central and peripheral nervous systems. This peptide mediates anumber of physiological effects through its various receptor subtypes.Studies in animals have shown that neuropeptide Y is a powerful stimulusof food intake, and it has been demonstrated that activation ofneuropeptide Y Y5 receptors results in hyperphagia and decreasedthermogenesis. Therefore compounds that antagonise neuropeptide Y at theY5 receptor subtype represent an approach to the treatment of eatingdisorders such as obesity and hyperphagia.

The current approach is aiming at medical intervention to induce weightloss or prevention of weight gain. This is achieved by interfering withappetite control, which is mediated by the Hypothalamus, an importantbrain region proven to control food intake. Herein, neuropeptide Y (NPY)has been proven to be one of the strongest central mediators of foodintake in several animal species. Increased NPY levels result inprofound food intake. Various receptors of neuropeptide Y (NPY) havebeen described to play a role in appetite control and weight gain.Interference with these receptors is likely to reduce appetite andconsequently weight gain. Reduction and long-term maintenance of bodyweight can also have beneficial consequences on co-associated riskfactors such as arthritis, cardiovascular diseases, diabetes and renalfailure.

SUMMARY OF THE INVENTION

The present invention provides novel thiazole derivatives useful asneuropeptide Y (NPY) receptor ligands, particularly neuropeptide Y (NPY)antagonists. The invention is concerned especially with compounds offormula

and pharmaceutically acceptable salts and esters thereof;wherein

-   R¹ is aryl or heteroaryl, wherein at least one of the two meta    positions of each aryl and heteroaryl group is substituted with R⁵;-   R² is hydrogen, alkyl or cycloalkyl;-   R³ is cycloalkyl, aryl or heteroaryl, wherein at least one of the    two ortho positions of each cycloalkyl, aryl and heteroaryl group is    substituted with R⁶;-   R⁴ is hydrogen, alkyl or cycloalkyl;-   R⁵ is hydrogen, cyano, trifluoromethyl, alkyl-SO₂—, amino-SO₂—,    halogen, alkoxy, alkylcarbonyl or aminocarbonyl;-   R⁶ is hydrogen, halogen, cyano, nitro, trifluoromethyl, alkyl,    alkoxy, hydroxy or alkoxycarbonyl; and-   with the proviso that one of R⁵ and R⁶ is not hydrogen.

The compounds of formula I and their pharmaceutically acceptable saltsare neuropeptide ligands, for example neuropeptide receptor antagonistsand in particular, they are selective neuropeptides Y Y5 receptorantagonists. The compounds of formula I and their pharmaceuticallyacceptable salts and esters can be used in the prophylaxis or treatmentof arthritis, cardiovascular diseases, diabetes, renal failure andparticularly eating disorders and obesity.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel thiazole derivatives useful asneuropeptide Y (NPY) receptor ligands, particularly neuropeptide Y (NPY)antagonists. The invention is concerned especially with compounds offormula

and pharmaceutically acceptable salts and esters thereof;wherein

-   R¹ is aryl or heteroaryl, wherein at least one of the two meta    positions of each aryl and heteroaryl group is substituted with R⁵;-   R² is hydrogen, alkyl or cycloalkyl;-   R³ is cycloalkyl, aryl or heteroaryl, wherein at least one of the    two ortho positions of each cycloalkyl, aryl and heteroaryl group is    substituted with R⁶;-   R⁴ is hydrogen, alkyl or cycloalkyl;-   R⁵ is hydrogen, cyano, trifluoromethyl, alkyl-SO₂—, amino-SO₂—,    halogen, alkoxy, alkylcarbonyl or aminocarbonyl;-   R⁶ is hydrogen, halogen, cyano, nitro, trifluoromethyl, alkyl,    alkoxy, hydroxy or alkoxycarbonyl; and-   with the proviso that one of R⁵ and R⁶ is not hydrogen.

The compounds of formula I and their pharmaceutically acceptable saltsare neuropeptide ligands, for example neuropeptide receptor antagonistsand in particular, they are selective neuropeptides Y Y5 receptorantagonists. The compounds of formula I and their pharmaceuticallyacceptable salts and esters can be used in the prophylaxis or treatmentof arthritis, cardiovascular diseases, diabetes, renal failure andparticularly eating disorders and obesity.

In the present description the term “alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 8carbon atoms, preferably a straight or branched-chain alkyl group with 1to 6 carbon atoms and particularly preferred a straight orbranched-chain alkyl group with 1 to 4 carbon atoms Examples ofstraight-chain and branched C₁-C₈ alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls,the isomeric hexyls, the isomeric heptyls and the isomeric octyls,preferably methyl and ethyl and most preferred methyl.

The term “cycloalkyl”, alone or in combination, signifies a cycloalkylring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to6 carbon atoms. Examples of C₃-C₈ cycloalkyl are cyclopropyl,methyl-cyclopropyl, dimethylcyclopropyl, cydobutyl, methyl-cyclobutyl,cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl,dimethyl-cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl.

The term “alkoxy”, alone or in combination, signifies a group of theformula alkyl-O— in which the term “alkyl” has the previously givensignificance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec. butoxy and tert.butoxy, 2-hydroxyethoxy,2-methoxyethoxypreferably methoxy and ethoxy and most preferred methoxy.

The term “aryl”, alone or in combination, signifies a phenyl or naphthylgroup, preferably a phenyl group which optionally carries one or moresubstituents each independently selected from halogen, trifluoromethyl,amino, alkyl, alkoxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl,methylendioxy, carboxy, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro, alkyl-SO₂—,amino-SO₂—, and cycloalkyl. Preferred is phenyl or naphthyl,particularly phenyl optionally substituted with substituentsindependently selected from cyano, trifluoromethyl, alkyl-SO₂—,amino-SO₂—, halogen, alkoxy, hydroxy, amino, cycloalkyl, alkylcarbonyl,aminocarbonyl, nitro, alkyl and alkoxycarbonyl.

The term “aralkyl”, alone or in combination, signifies an alkyl orcycloalkyl group as previously defined in which one hydrogen atom hasbeen replaced by an aryl group as previously defined. Preferred arebenzyl, benzyl substituted with hydroxy, alkoxy or halogen, preferablyfluorine. Particularly preferred is benzyl.

The term “heteroaryl”, alone or in combination, signifies aromatic 5- to10-membered heterocycle which comprises one or more, preferably one ortwo, particularly preferred one hetero atom selected from nitrogen,oxygen and sulfur, wherein nitrogen is preferred. It can be substitutedon one or more carbon atoms by a group selected from cyano,trifluoromethyl, alkyl-SO₂—, amino-SO₂—, halogen, alkoxy, hydroxy,amino, cycloalkyl, alkylcarbonyl, aminocarbonyl nitro, alkyl, andalkoxycarbonyl. Preferred heteroaryl cycles are pyridyl, pyrazinyl andthiophenyl optionally substituted by one or more, preferably one or twosubstituents independently selected from cyano, trifluoromethyl,alkyl-SO₂—, amino-SO₂—, halogen, alkoxy, alkylcarbonyl, aminocarbonyl,nitro, alkyl and alkoxycarbonyl.

The term “amino”, alone or in combination, signifies a primary,secondary or tertiary amino group bonded via the nitrogen atom, with thesecondary amino group carrying an alkyl or cycloalkyl substituent andthe tertiary amino group carrying two similar or different alkyl orcycloalkyl substituents or the two nitrogen substituents togetherforming a ring. Examples of amino include —NH₂, methylamino, ethylamino,dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl orpiperidino etc., preferably amino, dimethylamino and diethylamino andparticularly primary amino.

The term “halogen” signifies fluorine, chlorine, bromine or iodine andpreferably fluorine, chlorine or bromine.

The term “carbonyl”, alone or in combination signifies the —C(O)— group.

The term “nitro”, alone or in combination signifies the —NO₂ group.

The term “cyano”, alone or in combination signifies the group —CN.

The term “meta position” as used in the definition of substituent R¹means that substituent R⁵ is attached to the aryl or heteroaryl cycle inmeta position to the atom of the aryl or heteroaryl cycle which isattached to the —NR²— group. For example in case aryl means phenyl inthe definition of R¹ the substituent(s) R⁵ is (are) attached to thephenyl cycle according to the following formulae:

According to the definition of substituent R¹ the aryl or heteroarylcycle is substituted by one or two R⁵ substituents. In case two R⁵substituents are attached to the aryl or heteroaryl cycle the two R⁵substituents are the same or are different. Preferably, both R⁵substituents are the same. The R⁵ substituents are independentlyselected from hydrogen, cyano, trifluoromethyl, alkyl-SO₂—, amino-SO₂—,halogen, alkoxy, alkylcarbonyl and aminocarbonyl.

The term “ortho position” as used in the definition of substituent R³means that substituent R⁶ is attached to the cycloalkyl, aryl orheteroaryl cycle in ortho position to the atom of the cycloalkyl, arylor heteroaryl which is attached to the carbonyl group. For example incase aryl means phenyl in the definition of R³ the substituent(s) R⁶ is(are) attached to the phenyl cycle according to the following formulae:

According to the definition of substituent R³ the cycloalkyl, aryl orheteroaryl cycle can be substituted by one or two R⁶ substituents. Incase two R⁶ substituents are attached to the cycloalkyl, aryl orheteroaryl cycle the two R⁶ substituents can be the same or can bedifferent. Preferably, both R⁶ substituents are the same.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, preferably hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition these salts may be preparedform addition of an inorganic base or an organic base to the free acid.Salts derived from an inorganic base include, but are not limited to,the sodium, potassium, lithium, ammonium, calcium, magnesium salts andthe like. Salts derived from organic bases include, but are not limitedto salts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polymine resins and the like.The compound of formula I can also be present in the form ofzwitterions. Particularly preferred pharmaceutically acceptable salts ofcompounds of formula I are the hydrochloride salts.

The compounds of formula I can also be solvated, e.g. hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The termpharmaceutically acceptable salts also includes physiologicallyacceptable solvates.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention. Forexample, esters may be formed wherein aryl is substituted with carboxy,or wherein aryl, aralkyl or heteroaryl is substituted with hydroxy.

The term “lipase inhibitor” refers to compounds which are capable ofinhibiting the action of lipases, for example gastric and pancreaticlipases. For example orlistat and lipstatin as described in U.S. Pat.No. 4,598,089 are potent inhibitor of lipases. Lipstatin is a naturalproduct of microbial origin, and orlistat is the result of ahydrogenation of lipstatin. Other lipase inhibitors include a class ofcompound commonly referred to as panclicins. Panclicins are analogues oforlistat (Mutoh et al, 1994). The term “lipase inhibitor” refers also topolymer bound lipase inhibitors for example described in InternationalPatent Application WO99/34786 (Geltex Pharmaceuticals Inc.). Thesepolymers are characterized in that they have been substituted with oneor more groups that inhibit lipases. The term “lipase inhibitor” alsocomprises pharmaceutically acceptable salts of these compounds. The term“lipase inhibitor” preferably refers to orlistat.

Orlistat is a known compound useful for the control or prevention ofobesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul. 1,1986, which also discloses processes for making orlistat and U.S. Pat.No. 6,004,996, which discloses appropriate pharmaceutical compositions.Further suitable pharmaceutical compositions are described for examplein International Patent Applications WO 00/09122 and WO 00/09123.Additional processes for the preparation of orlistat are disclosed inEuropean Patent Applications Publication Nos. 185,359, 189,577, 443,449,and 524,495.

Orlistat is preferably orally administered from 60 to 720 mg per day individed doses two to three times per day. Preferred is wherein from 180to 360 mg, most preferably 360 mg per day of a lipase inhibitor isadministered to a subject, preferably in divided doses two or,particularly, three times per day. The subject is preferably an obese oroverweight human, i.e. a human with a body mass index of 25 or greater.Generally, it is preferred that the lipase inhibitor be administeredwithin about one or two hours of ingestion of a meal containing fat.Generally, for administering a lipase inhibitor as defined above it ispreferred that treatment be administered to a human who has a strongfamily history of obesity and has obtained a body mass index of 25 orgreater.

Orlistat can be administered to humans in conventional oralcompositions, such as, tablets, coated tablets, hard and soft gelatincapsules, emulsions or suspensions. Examples of carriers which can beused for tablets, coated tablets, dragees and hard gelatin capsules arelactose, other sugars and sugar alcohols like sorbitol, mannitol,maltodextrin, or other fillers; surfactants like sodium lauryle sulfate,Brij 96, or Tween 80; disintegrants like sodium starch glycolate, maizestarch or derivatives thereof; polymers like povidone, crospovidone;talc; stearic acid or its salts and the like. Suitable carriers for softgelatin capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Moreover, the pharmaceuticalpreparations can contain preserving agents, solubilizers, stabilizingagents, wetting agents, emulsifying agents, sweetening agents, coloringagents, flavoring agents, salts for varying the osmotic pressure,buffers, coating agents and antioxidants. They can also contain stillother therapeutically valuable substances. The formulations mayconveniently be presented in unit dosage form and may be prepared by anymethods known in the pharmaceutical art. Preferably, orlistat isadministered according to the formulation shown in the Examples and inU.S. Pat. No. 6,004,996, respectively.

The compounds of formula I can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereioisomers, mixtures of diastereo-isomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

Preferred are the compounds of formula I and pharmaceutically acceptablesalts thereof, particularly the compounds of formula I.

Further preferred are compound of formula I, wherein

-   R¹ is aryl or heteroaryl, wherein at least one of the two meta    positions of each aryl and heteroaryl group is substituted with R⁵;-   R² is hydrogen, alkyl or cycloalkyl;-   R³ is cycloalkyl, aryl or heteroaryl, wherein at least one of the    two ortho positions of each cycloalkyl, aryl and heteroaryl group is    substituted with R⁶;-   R⁴ is hydrogen, alkyl or cycloalkyl;-   R⁵ is cyano, trifluoromethyl, alkyl-SO₂—, amino-SO₂—, halogen,    alkoxy, alkylcarbonyl or aminocarbonyl;-   R⁶ is halogen, cyano, nitro, trifluoromethyl, alkyl, alkoxy, hydroxy    or alkoxycarbonyl;    and pharmaceutically acceptable salts and esters thereof.

Further preferred are the compounds of formula I, wherein R¹ is aryl orheteroaryl and, wherein one of the two meta positions of each aryl andheteroaryl group is substituted with R⁵, wherein R⁵ is defined asbefore.

Also preferred are the compounds of formula I, wherein R³ is cycloalkyl,aryl or heteroaryl and wherein one of the two ortho positions of eachcycloalkyl, aryl and heteroaryl group is substituted with R⁶, wherein R⁶is defined as before.

Also preferred are compounds according to formula I, wherein R⁴ ishydrogen or methyl. Particularly preferred are those compounds offormula I, wherein R⁴ is hydrogen.

Other preferred compounds of formula I are those, wherein R² ishydrogen.

Further preferred compounds of formula I are those, wherein R³ iscylohexyl, naphthyl, phenyl, pyridyl, pyrazinyl or thiophenyl, whereinat least one of the two ortho positions of each cylohexyl, naphthyl,phenyl, pyridyl, pyrazinyl and thiophenyl group is substituted with R⁶,wherein R⁶ is defined as before.

Another preferred embodiment of the present invention is the compoundsaccording to formula I, wherein R³ is phenyl or pyridyl and wherein atleast one of the two ortho positions of each phenyl and pyridyl group issubstituted with R⁶, wherein R⁶ is defined as before.

Also preferred are compounds according to formula I, wherein R¹ isphenyl or pyridyl and, wherein at least one of the two meta positions ofeach phenyl or pyridyl group is substituted with R⁵ and, wherein R⁵ isdefined as before.

Another preferred embodiment of the present invention is the compoundsof formula I, wherein R¹ is phenyl or pyridyl and wherein one of the twometa positions of each phenyl or pyridyl group is substituted withcyano, trifluoromethyl, alkyl-SO₂—, amino-SO₂—, halogen, alkoxy,alkylcarbonyl or aminocarbonyl.

Also preferred are compounds of formula I, wherein R⁵ is cyano,trifluoromethyl, alkyl-SO₂—, amino-SO₂—, halogen, alkoxy, alkylcarbonylor aminocarbonyl.

Another preferred aspect of the present invention are the compounds offormula I, wherein R⁵ is cyano, trifluoromethyl, alkyl-SO₂—, amino-SO₂—or alkylcarbonyl.

Further preferred are the compounds of formula I, wherein R⁵ is cyano,trifluoromethyl, methyl-SO₂—, NH₂—SO₂— or methylcarbonyl.

Also preferred are the compounds of formula I, wherein R⁶ is halogen,cyano, nitro, trifluoromethyl, alkyl, alkoxy, hydroxy or alkoxycarbonyl.

Further preferred are the compounds of formula I, wherein R⁶ is halogen,trifluoromethyl or alkyl.

Examples of preferred compounds of formula (I) are:

-   1. 3-[5-(Naphthalene-2-carbonyl)-thiazol-2-ylamino]-benzonitrile;-   2. 3-(5-Benzoyl-thiazol-2-ylamino)-benzonitrile;-   3. 3-[5-(4-Methyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   4.    [2-(3-Methanesulfonyl-phenylamino)-thiazol-5-yl]-phenyl-methanone;-   5. [2-(3-Methoxy-phenylamino)-thiazol-5-yl]-phenyl-methanone;-   6.    Phenyl-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   7. 3-[5-(3-Methoxy-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   8. 3-[5-(4-Fluoro-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   9. 3-[5-(4-Chloro-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   10.    [2-(3,5-Dichloro-phenylamino)-thiazol-5-yl]-(2-fluoro-phenyl)-methanone;-   11.    (2-Chloro-phenyl)-[2-(3,5-dichloro-phenylamino)-thiazol-5-yl]-methanone;-   12. 3-[5-(4-Bromo-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   13. 3-[5-(3-Chloro-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   14. 3-[5-(2-Fluoro-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   15. 3-[5-(3-Fluoro-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   16. 3-[5-(2-Methoxy-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   17.    3-[5-(3-Trifluoromethyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   18. 3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   19. 3-[5-(3-Bromo-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   20.    [2-(4-Chloro-phenylamino)-thiazol-5-yl]-(2-fluoro-phenyl)-methanone;-   21.    (2-Chloro-phenyl)-[2-(4-chloro-phenylamino)-thiazol-5-yl]-methanone;-   22.    p-Tolyl-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   23.    (4-Fluoro-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   24.    (3-Methoxy-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   25.    (3-Chloro-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   26.    (2-Fluoro-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   27.    (3-Fluoro-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   28.    (2-Methoxy-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   29.    (2-Chloro-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   30.    (3-Bromo-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   31. [2-(Pyridin-4-ylamino)-thiazol-5-yl]-o-tolyl-methanone;-   32.    (2,4-Dichloro-phenyl)-[2-(pyridin-4-ylamino)-thiazol-5-yl]-methanone;-   33.    (2,4-Dimethyl-phenyl)-[2-(pyridin-4-ylamino)-thiazol-5-yl]-methanone;-   34. (2-Nitro-phenyl)-[2-(pyridin-4-ylamino)    -thiazol-5-yl]-methanone;-   35. 3-[5-(Pyridine-2-carbonyl)-thiazol-2-ylamino]-benzonitrile;-   36. 3-[5-(Pyridine-3-carbonyl)-thiazol-2-ylamino]-benzonitrile;-   37. 3-[5-(Pyridine-4-carbonyl)-thiazol-2-ylamino]-benzonitrile;-   38. 3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   39. 3-(5-Cyclohexanecarbonyl-thiazol-2-ylamino)-benzonitrile;-   40. 3-[5-(2,4-Dichloro-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   41. 3-[5-(2,4-Dimethyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   42. 3-[5-(2-Nitro-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   43.    (2-Fluoro-phenyl)-[2-(3-methoxy-phenylamino)-thiazol-5-yl]-methanone;-   44. [2-(3-Methoxy-phenylamino)-thiazol-5-yl]-o-tolyl-methanone;-   45.    (2,4-Dimethyl-phenyl)-[2-(3-methoxy-phenylamino)-thiazol-5-yl]-methanone;-   46.    [2-(3-Methoxy-phenylamino)-thiazol-5-yl]-(2-nitro-phenyl)-methanone;-   47.    Pyridin-4-yl-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   48.    o-Tolyl-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   49.    Cyclohexyl-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   50.    (2,4-Dichloro-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   51.    (2,4-Dimethyl-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   52.    (2-Nitro-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   53.    (2-Fluoro-phenyl)-[2-(3-fluoro-phenylamino)-thiazol-5-yl]-methanone;-   54. [2-(3-Fluoro-phenylamino)-thiazol-5-yl]-o-tolyl-methanone;-   55.    (2-Chloro-phenyl)-[2-(3-fluoro-phenylamino)-thiazol-5-yl]-methanone;-   56. [2-(3-Bromo-phenylamino)-thiazol-5-yl]-phenyl-methanone;-   57. [2-(3-Bromo-phenylamino)-thiazol-5-yl]-o-tolyl-methanone;-   58.    [2-(3-Bromo-phenylamino)-thiazol-5-yl]-(2-chloro-phenyl)-methanone;-   59.    [2-(3-Bromo-phenylamino)-thiazol-5-yl]-(2,4-dimethyl-phenyl)-methanone;-   60. 1-{3-[5-(2-Fluoro-benzoyl)-thiazol-2-ylamino]-phenyl}-ethanone;-   61. 1-{3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-ethanone;-   62. 1-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-phenyl}-ethanone;-   63.    1-{3-[5-(2,4-Dimethyl-benzoyl)-thiazol-2-ylamino]-phenyl}-ethanone;-   64.    (2-Fluoro-phenyl)-[2-(pyridin-3-ylamino)-thiazol-5-yl]-methanone;-   65. [2-(Pyridin-3-ylamino)-thiazol-5-yl]-o-tolyl-methanone;-   66.    (2-Chloro-phenyl)-[2-(pyridin-3-ylamino)-thiazol-5-yl]-methanone;-   67.    3-[5-(3-Methyl-pyrazine-2-carbonyl)-thiazol-2-ylamino]-benzonitrile;-   68.    3-[5-(3-Ethyl-pyrazine-2-carbonyl)-thiazol-2-ylamino]-benzonitrile;-   69.    3-[5-(3-Methyl-thiophene-2-carbonyl)-thiazol-2-ylamino]-benzonitrile;-   70. 3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   71.    3-[5-(2-Trifluoromethyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   72.    3-[5-(3-Methyl-pyridine-2-carbonyl)-thiazol-2-ylamino]-benzonitrile;-   73.    3-[5-(2-Methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-benzonitrile;-   74.    3-[5-(2,5-Dimethyl-thiophene-3-carbonyl)-thiazol-2-ylamino]-benzonitrile;-   75.    (3-Methyl-thiophen-2-yl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   76.    (2-Ethyl-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   77.    (2-Trifluoromethyl-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   78.    (3-Methyl-pyridin-2-yl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   79.    (2,5-Dimethyl-thiophen-3-yl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   80. o-Tolyl-(2-m-tolylamino-thiazol-5-yl)-methanone;-   81. (2-Ethyl-phenyl)-(2-m-tolylamino-thiazol-5-yl)-methanone;-   82.    (2-m-Tolylamino-thiazol-5-yl)-(2-trifluoromethyl-phenyl)-methanone;-   83. (2-Fluoro-phenyl)-(2-m-tolylamino-thiazol-5-yl)-methanone;-   84. (2-Chloro-phenyl)-(2-m-tolylamino-thiazol-5-yl)-methanone;-   85. (2-Methoxy-phenyl)-(2-m-tolylamino-thiazol-5-yl)-methanone;-   86.    (2,5-Dimethyl-thiophen-3-yl)-(2-m-tolylamino-thiazol-5-yl)-methanone;-   87.    [2-(3-Methanesulfonyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone;-   88.    (2-Ethyl-phenyl)-[2-(3-methanesulfonyl-phenylamino)-thiazol-5-yl]-methanone;-   89.    [2-(3-Methanesulfonyl-phenylamino)-thiazol-5-yl]-(2-trifluoromethyl-phenyl)-methanone;-   90.    (2-Chloro-phenyl)-[2-(3-methanesulfonyl-phenylamino)-thiazol-5-yl]-methanone;-   91.    [2-(3-Methanesulfonyl-phenylamino)-thiazol-5-yl]-(4-methyl-pyridin-3-yl)-methanone;-   92.    (2,5-Dimethyl-thiophen-3-yl)-[2-(3-methanesulfonyl-phenylamino)-thiazol-5-yl]-methanone;-   93.    4-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-pyridine-2-carbonitrile;-   94.    4-[5-(3-Methyl-pyridine-2-carbonyl)-thiazol-2-ylamino]-pyridine-2-carbonitrile;-   95.    4-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-pyridine-2-carbonitrile;-   96.    4-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-pyridine-2-carbonitrile;-   97.    4-[5-(2-Fluoro-benzoyl)-thiazol-2-ylamino]-pyridine-2-carbonitrile;-   98. 3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide;-   99. 3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide;-   100.    3-[5-(4-Hydroxy-2-methyl-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide;-   101.    3-[5-(2-Trifluoromethyl-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide;-   102. 3-[5-(2-Fluoro-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide;-   103. 3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide;-   104. 3-[5-(2-Methoxy-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide;-   105. 3-[5-(3-Fluoro-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide;-   106. 3-[5-(3-Chloro-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide;-   107.    3-[5-(4-Methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-benzenesulfonamide;-   108.    3-[5-(3-Methyl-pyridine-2-carbonyl)-thiazol-2-ylamino]-benzenesulfonamide;-   109.    3-[5-(3-Ethyl-pyrazine-2-carbonyl)-thiazol-2-ylamino]-benzenesulfonamide;-   110.    3-[5-(3-Methyl-thiophene-2-carbonyl)-thiazol-2-ylamino]-benzenesulfonamide;-   111.    3-[4-Methyl-5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-benzonitrile    and-   112. Phenyl-(2-m-tolylamino-thiazol-5-yl)-methanone.

Examples of particularly preferred compounds of formula (I) are:

-   3-[5-(2-Fluoro-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   (2-Chloro-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   o-Tolyl-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;-   1-{3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-ethanone;-   3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   3-[5-(2-Trifluoromethyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;-   3-[5-(3-Methyl-pyridine-2-carbonyl)-thiazol-2-ylamino]-benzonitrile;-   [2-(3-Methanesulfonyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone;-   (2-Ethyl-phenyl)-[2-(3-methanesulfonyl-phenylamino)-thiazol-5-yl]-methanone;-   4-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-pyridine-2-carbonitrile;-   4-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-pyridine-2-carbonitrile;-   3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide; and-   3-[5-(2-Trifluoromethyl-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide.

The preparation of compounds of formula I of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following Schemes. The skills requiredfor carrying out the reaction and purification of the resulting productsare known to those in the art. The substituents and indices used in thefollowing description of the processes have the significance given aboveunless indicated to the contrary.

Compounds of general formula IA (R⁴═H) can be prepared according toscheme 1 as follows:

-   a) Thioureas IB, either commercially available or accessible via    various procedures described in literature, are conveniently reacted    with N,N-dimethylformamide dimethyl acetal in the presence or the    absence of a solvent. There is no particular restriction on the    nature of the solvent to be employed, provided that it has no    adverse effect on the reaction or the reagents involved and that it    can dissolve the reagents, at least to some extent. Examples for    suitable solvents include: DMF and dioxane and the like. The    reaction can take place over a wide range of temperatures, and the    precise reaction temperature is not critical to the invention. We    find it convenient to carry out the reaction with heating from    ambient temperature to reflux. The time required for the reaction    may also vary widely, depending on many factors, notably the    reaction temperature and the nature of the reagents. However, a    period of from 0.5 h to several days will usually suffice to yield    the Dimethylaminomethylene-thioureido derivatives IC. For reaction    conditions described in literature affecting such a reaction see for    example: Heterocycles 11, 313-318; 1978.-   b) Dimethylaminomethylene-thioureido derivatives IC can be converted    to thiazole derivatives IA (R⁴═H) by reaction of IA with    α-bromoketones ID (a known compound or compound prepared by known    methods. The source for α-bromoketones employed is indicated as    appropriate) in a solvent such as ethanol, and the like, in the    presence or the absence of a base. There is no particular    restriction on the nature of the solvent to be employed, provided    that it has no adverse effect on the reaction or the reagents    involved and that it can dissolve the reagents, at least to some    extent. Examples for suitable solvents include: dichloromethane,    chloroform, or dioxane, methanol, ethanol and the like. There is no    particular restriction on the nature of the base used in this stage,    and any base commonly used in this type of reaction may equally be    employed here. Examples of such bases include triethylamine and    diisopropylethylamine, and the like. The reaction can take place    over a wide range of temperatures, and the precise reaction    temperature is not critical to the invention. We find it convenient    to carry out the reaction with heating from ambient temperature to    reflux. The time required for the reaction may also vary widely,    depending on many factors, notably the reaction temperature and the    nature of the reagents. However, a period of from 0.5 h to several    days will usually suffice to yield the thiazole derivatives IA. For    reaction conditions described in literature affecting such a    reaction see for example: J. Heterocycl. Chem., 16 (7),    1377-83; 1979. The resulting compound of formula IA (R⁴═H, R²═H) is    a compound of the present invention and may be the desired product;    alternatively it may be subjected to consecutive reactions like    removal of a protecting group by methods described widely in    literature to yield the desired thiazole derivatives IA. However,    the resulting compound of formula IA is a compound of the present    invention and may be the desired product; alternatively it may be    subjected to consecutive reactions. Introduction of R²=alkyl or    cycloalky (in the case R²═H) in IA can be affected by reductive    amination of IA with the respective aldehyde under reducing    conditions in a solvent. There is no particular restriction on the    nature of the solvent to be employed, provided that it has no    adverse effect on the reaction or the reagents involved and that it    can dissolve the reagents, at least to some extent. Examples for    suitable solvents include: dichloromethane, chloroform, dioxane,    THF, and the like. There is no particular restriction on the nature    of the reducing agent used in this stage, and any reducing agent    commonly used in this type of reaction may equally be employed here.    Examples of such reducing agents include NaBH₄, NaCNBH₃, and the    like. The reaction can take place over a wide range of temperatures,    and the precise reaction temperature is not critical to the    invention. We find it convenient to carry out the reaction with    heating from ambient temperature to reflux. The time required for    the reaction may also vary widely, depending on many factors,    notably the reaction temperature and the nature of the reagents.    However, a period of from 0.5 h to several days will usually suffice    to yield the desired thiazole derivatives IA (R²=alkyl or    cycloalkyl). For reaction conditions described in literature    affecting a reductive amination see for example: Reductive amination    in: A Guide to Functional Group Preparations, 2nd Edition,    Richard C. Larock. John Wiley & Sons, New York, N.Y. 1999. The    resulting compound of formula IA (R²=alkyl or cycloalkyl) is a    compound of the present invention and may be the desired product;    alternatively it may be subjected to consecutive reactions like    removal of a protecting group by methods described widely in    literature to yield the desired thiazole derivatives IA.

Compounds of general formula IA (R⁴=alkyl or cycloalkyl) can be preparedaccording to scheme 2 as follows:

-   a) Thioisocyanates IIA are commercially available or can be prepared    from suitable starting materials according to methods known in the    art. The elaboration of the thioisocyanate-moiety like in IIA to a    thioureido-moiety like in IIC can be affected by methods described    in literature. For example compounds of the general formula IIA are    condensed with an amidine of general formula IIB or their salts    (R⁴=alkyl , cycloakly), a known compound or compound prepared by    known methods, in a solvent such as THF, or the like, and a base,    such as NaOH, or the like. There is no particular restriction on the    nature of the solvent to be employed, provided that it has no    adverse effect on the reaction or the reagents involved and that it    can dissolve the reagents, at least to some extent. Examples for    suitable solvents include: dichloromethane, chloroform, dioxane, THF    and the like. There is no particular restriction on the nature of    the base used in this stage, and any base commonly used in this type    of reaction may equally be employed here. Examples of such bases    include NaOHaq., KOHaq, NEt₃, and the like. The reaction can take    place over a wide range of temperatures, and the precise reaction    temperature is not critical to the invention. We find it convenient    to carry out the reaction from 0° C. to heating to reflux    temperature of the solvent. The time required for the reaction may    also vary widely, depending on many factors, notably the reaction    temperature and the nature of the reagents. However, a period of    from 0.5 h to several days will usually suffice to yield the    thioureido derivatives IIC. For reaction conditions described in    literature affecting such a reaction see for example: C. R. Seances    Acad. Sci., Ser. 2, 294 (19), 1183-6; 1982.    Dimethylaminomethylene-thioureido derivatives IIC can be converted    to thiazole derivatives IID (R⁴=alkyl, cycloalkyl) by reaction of    IIC with α-bromoketones ID (a known compound or compound prepared by    known methods. The source for α-bromoketones employed is indicated    as appropriate) in a solvent such as ethanol, and the like, in the    presence or the absence of a base. There is no particular    restriction on the nature of the solvent to be employed, provided    that it has no adverse effect on the reaction or the reagents    involved and that it can dissolve the reagents, at least to some    extent. Examples for suitable solvents include: dichloromethane,    chloroform, DMF, dioxane, methanol, ethanol and the like. There is    no particular restriction on the nature of the base used in this    stage, and any base commonly used in this type of reaction may    equally be employed here. Examples of such bases include    triethylamine and diisopropylethylamine, and the like. The reaction    can take place over a wide range of temperatures, and the precise    reaction temperature is not critical to the invention. We find it    convenient to carry out the reaction with heating from ambient    temperature to reflux. The time required for the reaction may also    vary widely, depending on many factors, notably the reaction    temperature and the nature of the reagents. However, a period of    from 0.5 h to several days will usually suffice to yield the    thiazole derivatives IID. For reaction conditions described in    literature affecting such a reaction see for example: Org. Chem., 65    (21), 7244-7247; 2000. The resulting compound of formula IID    (R⁴=alkyl or cycloalkyl, R²═H) is a compound of the present    invention and may be the desired product; alternatively it may be    subjected to consecutive reactions like removal of a protecting    group by methods described widely in literature to yield the desired    thiazole derivatives IA (R⁴=alkyl or cycloalkyl, R²═H). However, the    resulting compound of formula IID is a compound of the present    invention and may be the desired product; alternatively it may be    subjected to consecutive reactions. Introduction of R²=alkyl or    cycloalky can be affected by reductive amination of IID with the    respective aldehyde under reducing conditions in a solvent. There is    no particular restriction on the nature of the solvent to be    employed, provided that it has no adverse effect on the reaction or    the reagents involved and that it can dissolve the reagents, at    least to some extent. Examples for suitable solvents include:    dichloromethane, chloroform, dioxane, THF, and the like. There is no    particular restriction on the nature of the reducing agent used in    this stage, and any reducing agent commonly used in this type of    reaction may equally be employed here. Examples of such reducing    agents include NaBH₄, NaCNBH₃, and the like. The reaction can take    place over a wide range of temperatures, and the precise reaction    temperature is not critical to the invention. We find it convenient    to carry out the reaction with heating from ambient temperature to    reflux. The time required for the reaction may also vary widely,    depending on many factors, notably the reaction temperature and the    nature of the reagents. However, a period of from 0.5 h to several    days will usually suffice to yield the thiazole derivatives IA    (R⁴=alkyl or cycloalkyl R²=alkyl or cycloalkyl). For reaction    conditions described in literature affecting a reductive amination    see for example: Reductive amination in: A Guide to Functional Group    Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New    York, N.Y. 1999. The resulting compound of formula IA (R⁴=alkyl or    cycloalkyl, R²=alkyl or cycloalkyl) is a compound of the present    invention and may be the desired product; alternatively it may be    subjected to consecutive reactions like removal of a protecting    group by methods described widely in literature to yield the desired    thiazole derivatives IA (R⁴=alkyl or cycloalkyl, R²=alkyl or    cycloalkyl).

The conversion of a compound of formula I into a pharmaceuticallyacceptable salt can be carried out by treatment of such a compound withan inorganic acid, for example a hydrohalic acid, such as, for example,hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid etc., or with an organic acid, such as, for example,acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid,methanesulfonic acid or p-toluenesulfonic acid. The correspondingcarboxylate salts can also be prepared from the compounds of formula Iby treatment with physiologically compatible bases.

The conversion of compounds of formula I into pharmaceuticallyacceptable esters or amides can be carried out e.g. by treatment ofsuited amino or hydroxyl groups present in the molecules with ancarboxylic acid such as acetic acid, with a condensating reagent such asbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) or N,N-dicylohexylcarbodiimide (DCCI) to produce the carboxylicester or carboxylic amide.

A preferred process for the preparation of a compound of formula Icomprises one of the following reactions

-   a) reaction of a compound according to formula IIC in the presence    of a compound according to formula ID in order to obtain a compound    of formula I

wherein R¹ to R⁴ are defined as before;

-   b) reaction of a compound according to formula IID in the presence    of R²—CHO in order to obtain a compound of formula I

wherein R¹, R³ and R⁴ are defined as before and R² means alkyl orcycloalkyl. Preferred is the above reaction under reducing conditions,particularly in the presence of an reducing agent such as NaBH₄ orNaCNBH₃.

Preferred intermediates are:

-   1-Dimethylaminomethylene-3-(3-methanesulfonyl-phenyl)-thiourea;-   1-(2-Cyano-pyridin-4-yl)-3-dimethylaminomethylene-thiourea;-   1-Dimethylaminomethylene-3-(3-cyano-phenyl)-thiourea;-   1-Dimethylaminomethylene-3-pyridin-3-yl-thiourea;-   1-Dimethylaminomethylene-3-pyridin-4-yl-thiourea;-   1-Dimethylaminomethylene-3-(3-bromo-phenyl)-thiourea;-   1-Dimethylaminomethylene-3-(3-acetyl-phenyl)-thiourea;-   1-Dimethylaminomethylene-3-(3-acetyl-phenyl)-thiourea; and-   3-Thioureido-benzenesulfonamide

The compounds of formula I described above for use as therapeuticallyactive substances are a further object of the invention.

Also an object of the invention are compounds described above for theproduction of medicaments for the prophylaxis and therapy of illnesseswhich are caused by disorders associated with the NPY receptor,particularly for the production of medicaments for the prophylaxis andtherapy of arthritis, cardiovascular diseases, diabetes, renal failureand particularly eating disorders and obesity.

Likewise an object of the invention are pharmaceutical compositionscontaining a compound of formula I described above and a therapeuticallyinert carrier.

An object of the invention is also the use of the compounds describedabove for the production of medicaments, particularly for the treatmentand prophylaxis of arthritis, cardiovascular diseases, diabetes, renalfailure and particularly eating disorders and obesity.

A further object of the invention comprises compounds which aremanufactured according to one of the described processes.

A further object of the invention is a method for the treatment andprophylaxis of arthritis, cardiovascular diseases, diabetes, renalfailure and particularly eating disorders and obesity whereby aneffective amount of a compound described above is administered.

According to a further aspect of the invention there is provided amethod of treatment of obesity in a human in need of such treatmentwhich comprises administration to the human a therapeutically effectiveamount of a compound according to formula I and a therapeuticallyeffective amount of a lipase inhibitor, particularly preferred, whereinthe lipase inhibitor is orlistat. Also subject of the present inventionis the mentioned method, wherein the administration is simultaneous,separate or sequential.

A further preferred embodiment of the present invention is the use of acompound of the formula I in the manufacture of a medicament for thetreatment and prevention of obesity in a patient who is also receivingtreatment with a lipase inhibitor, particularly preferred, wherein thelipase inhibitor is orlistat.

Also an object of the invention are compounds described above for theproduction of medicaments for the prophylaxis and therapy of alcoholism.

A further object of the invention is a method for the treatment andprophylaxis of alcoholism.

ASSAY PROCEDURES Cloning of Mouse NPY5 Receptor cDNAs

The full-length cDNA encoding the mouse NPY5 (mNPY5) receptor wasamplified from mouse brain cDNA using specific primers, designed basedon the published sequence, and Pfu DNA-Polymerase. The amplificationproduct was subcloned into the mammalian expression vector pcDNA3 usingEco RI and XhoI restriction sites. Positive clones were sequenced andone clone, encoding the published sequence was selected for generationof stable cell clones. The sequence is published in Borowsky B., et al.,“Molecular Biology and Pharmacology of Multiple NPY Y5 Receptor SpeciesHomologs”, Regul. Pept. 75-76:45-53 (1998).

Stable Transfection

Human embryonic kidney 293 (HEK293) cells were transfected with 10 μgmNPY5 DNA using the lipofectamine reagent. Two days after transfection,geneticin selection (1 mg/ml) was initiated and several stable cloneswere isolated. One clone was further used for pharmacologicalcharacterization.

Radioligand Competition Binding

Human embryonic kidney 293 cells (HEK293), expressing recombinant mouseNPY5-receptor (mNPY5) were broken by three freeze/thawing cycles inhypotonic Tris buffer (5 mM, pH 7.4, 1 mM MgCl₂), homogenized andcentrifuged at 72,000×g for 15 min. The pellet was washed twice with 75mM Tris buffer, pH 7.4, containing 25 mM MgCl₂ and 250 mM sucrose, 0.1mM phenylmethylsulfonylfluoride and 0.1 mM 1,10-pheneanthrolin,resuspended in the same buffer and stored in aliquots at −80° C. Proteinwas determined according to the method of Lowry using bovine serumalbumine (BSA) as a standard.

Radioligand competition binding assays were performed in 250 μl 25 mMHepes buffer (pH 7.4, 2.5 mM CaCl₂, 1 mM MgCl₂, 1% bovine serumalbumine, and 0.01% NaN₃ containing 5 μg protein, 100 pM [¹²⁵I]labeledpeptide YY (PYY) and 10 μL DMSO containing increasing amounts ofunlabelled test compounds. After incubation for 1 h at 22° C., bound andfree ligand are separated by filtration over glass fibre filters. Nonspecific binding is assessed in the presence of 1 μM unlabelled PYY.Specific binding is defined as the difference between total binding andnon specific binding. IC₅₀ values are defined as the concentration ofantagonist that displaces 50% of the binding of [¹²⁵I]labeledneuropeptide Y. It is determined by linear regression analysis afterlogit/log transformation of the binding data.

Results obtained in the foregoing test using representative compounds ofthe invention as the test compounds are shown in the following table:

NPY5-R (mouse) Compound IC₅₀ (nM)(2-Chloro-phenyl)-[2-(3-trifluoromethyl- 8phenylamino)-thiazol-5-yl]-methanone (Example 29)3-[5-(4-Fluoro-benzoyl)-thiazol-2-ylamino]- 66 benzonitrile (Example 8)1-{3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]- 86 phenyl}-ethanone(Example 61)

The compounds as described above have IC₅₀ values below 1000 nM;preferred compounds have IC₅₀ values below 100 nM, particularly below 10nM. Most preferred compounds have IC₅₀ values below 2 nM. These resultshave been obtained by using the foregoing test.

The compounds of formula I and their pharmaceutically acceptable saltsand esters can be used as medicaments (e.g. in the form ofpharmaceutical preparations). The pharmaceutical preparations can beadministered internally, such as orally (e.g. in the form of tablets,coated tablets, dragees, hard and soft gelatin capsules, solutions,emulsions or suspensions), nasally (e.g. in the form of nasal sprays) orrectally (e.g. in the form of suppositories). However, theadministration can also be effected parentally, such as intramuscularlyor intravenously (e.g. in the form of injection solutions).

The compounds of formula I and their pharmaceutically acceptable saltsand esters can be processed with pharmaceutically inert, inorganic ororganic adjuvants for the production of tablets, coated tablets, dragéesand hard gelatin capsules. Lactose, corn starch or derivatives thereof,talc, stearic acid or its salts etc. can be used, for example, as suchadjuvants for tablets, dragées and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc. Suitable adjuvants for the production of solutions and syrups are,for example, water, polyols, saccharose, invert sugar, glucose, etc.Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc. Suitable adjuvants forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-solid or liquid polyols, etc.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

In accordance with the invention the compounds of formula I and theirpharmaceutically acceptable salts can be used for the prophylaxis andtreatment of arthritis, cardiovascular diseases, diabetes, renal failureand particularly eating disorders and obesity. The dosage can vary inwide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 0.1 mg to 20 mg per kg bodyweight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about300 mg per person), divided into preferably 1-3 individual doses, whichcan consist, for example, of the same amounts, should be appropriate. Itwill, however, be clear that the upper limit given above can be exceededwhen this is shown to be indicated. The invention is illustratedhereinafter by Examples, which have no limiting character.

EXAMPLES Example A1-Dimethylaminomethylene-3-(3-methanesulfonyl-phenyl)-thiourea

To a solution of 7.47 g (36 mmol) 3-Methylsulfonyl aniline hydrochlorideand 6.15 ml diisopropylethylamine in 75 ml THF was added 5.87 g (36mmol) benzoyl isothiocyanate dropwise and allowed to stir at roomtemperature for 1 h. The volatiles were removed under reduced pressureand the residue was treated with diethyl ether. The precipitate wasfiltered off, dried and dissolved in 100 ml THF and 130 ml methanol. 18g (130 mmol) potassium carbonate in 45 ml water was added and themixture was stirred for 24 h at room temperature. The reaction mixturewas concentrated and diluted with water. The precipitate was filteredoff, washed with diethyl ether/ethanol and dried. The crude solid wasdissolved in 50 ml dimethylformamide dimethyl acteal and heated for 3 hto 90° C. The precipitate was filtered off, washed with THF and dried toobtain 9.3 g (90%) of the title compound as white solid.

1-H-NMR (250 MHz-DMSO-d6): δ=10.75 (s, br, 1H, NH), 8.78 (s, 1H, H-2),8.57 (s, br, 1H, H-4), 7.72 (s, br, 1H, H-6), 7.53 (m, 2H, H-5/N═CH),3.23 (s, 3H, CH₃), 3.17 (s, 3H, OCH₃), 3.09 (s, 3H, OCH₃).

MS (m/e): 286.2 (M+H, 100%)

Example B(2-Fluoro-phenyl)-[2-(3-methanesulfonyl-phenylamino)-thiazol-5-yl]-methanone

To a solution of 37 mg (0.13 mmol)1-Dimethylaminomethylene-3-(3-methanesulfonyl-phenyl)-thiourea in 0.33ml DMF was added 28 mg (0.13 mmol) 2-Fluorophenacyl bromide and themixture was allowed to stir at room temperature for 16 h. 17 mg (0.13mmol) diisopropylethylamine was added and the mixture was subjected topreparative HPLC separation on reversed phase eluting with anacetonitrile/water gradient to yield 38.5 mg (79%) of the title compoundafter evaporation of the product fractions.

1-H-NMR (500 MHz-DMSO): δ=8.31 (s, br, 1H, H-2), 7.88 (s, br, 1H, H-4),7.78 (s, br, 1H, H-6), 7.63 (m, 4H, H-5/H-3′/H-6′, thiazole-H), 7.37 (m,2H, H-4′/H-5′), 3.37 (s, 3H, CH₃).

MS (m/e): 377.4 (M+H, 100%)

Example C 1-(2-Cyano-pyridin-4-yl) -3-dimethylaminomethylene-thiourea

The title compound, MS (m/e): 234.2 (M+H, 100%), was synthesisedaccording to the procedure in Example 1 from 2-Cyano-pyridin-4-yl-amine.

Example D 1-Dimethylaminomethylene-3-(3-cyano-phenyl)-thiourea

A mixture of 3 g (16.9 mmol) 1-(3-Cyanophenyl)-2-thiourea and 20 mlN,N-Dimethylformamide dimethyl acetal was heated to 100° C. for 1 h.After evaporation of the volatiles the precipitate was suspended in DCM,filtered and dried to yield 3.56 g (91%) of the title compound.

1-H-NMR (400 MHz-DMSO-d6): δ=10.6 (s, br, 1H, NH), 8.76 (s, 1H, CH),8.10 (d, br, 2H, Ar—H), 7.48 (s, br, 2H, Ar—H), 3.23 (s, 3H, CH₃), 3.08(s, 3H, CH₃).

MS (m/e): 233.1 (M+H, 100%)

Example E 1-Dimethylaminomethylene-3-pyridin-3-yl-thiourea

The title compound, MS (m/e): 209.2 (M+H, 100%), was synthesisedaccording to the procedure in Example 4 from pyridin-3-yl-thiourea anddimethylformamide dimethyl acetal.

Example F 1-Dimethylaminomethylene-3-pyridin-4-yl-thiourea

The title compound, MS (m/e): 209.2 (M+H, 100%), was synthesisedaccording to the procedure in Example 4 from pyridin-4-yl-thiourea anddimethylformamide dimethyl acetal.

Example G 1-Dimethylaminomethylene-3-(3-bromo-phenyl)-thiourea

The title compound, MS (m/e): 286.2 (M+H, 100%), was synthesisedaccording to the procedure in Example 4 from 3-bromophenyl-thiourea anddimethylformamide dimethyl acetal.

Example H 1-Dimethylaminomethylene-3-(3-acetyl-phenyl)-thiourea

The title compound, MS (m/e): 250.3 (M+H, 100%), was synthesisedaccording to the procedure in Example 4 from 3-acetylphenyl-thiourea anddimethylformamide dimethyl acetal.

Example I 1-Dimethylaminomethylene-3-(3-acetyl-phenyl)-thiourea

The title compound, MS (m/e): 222.3 (M+H, 100%), was synthesisedaccording to the procedure in Example 4 from 3-methylphenyl-thiourea anddimethylformamide dimethyl acetal.

Example J 2-Bromo-1-(3-ethyl-pyrazin-2-yl)-ethanone dihydrobromide

To a solution of 6 g (40 mmol) 1-(3-Ethyl-pyrazin-2-yl)-ethanone in 21ml HBr (33%) and 7 ml methanol was added 2 ml (40 mmol) bromine and themixture was heated to 60° C. for 3 h. After removal of the volatilesunder reduced pressure the residue was washed with diethyl ether andethyl acetate. 6.4 g (41%) of the title compound was obtained as greysolid.

MS (m/e): 229.1 (M+H, 100%).

Example K 2-Bromo-1-(3-methyl-pyrazin-2-yl)-ethanone dihydrobromide

The title compound was synthesised according to Example 4 from1-(3-Methyl-pyrazin-2-yl)-ethanone and HBr/bromine in 55% yield as greysolid. MS (m/e): 215.0 (M+H, 100%).

Example L 2-Bromo-1-(4-methyl-pyridin-3-yl)-ethanone hydrobromide

The title compound was synthesised according to Example 41-(4-methyl-pyridin-3-yl)-ethanone and HBr/bromine in 85% yield as greysolid. MS (m/e): 214.0 (M+H, 100%).

Example M 2-Bromo-1-(2-ethyl-phenyl)-ethanone

To a solution of 15.2 g (88 mmol) dibromethane in 120 ml THF at −75° C.was added 44 ml (88 mmol) of a 2M solution of LDA in THF andsubsequently 6.57 g (40 mmol) ethyl-benzoic acid methyl ester in 80 mlTHF. 37.5 ml of a 1.6 M n-butyl lithium solution in n-hexane was addedand after 30 min the mixture was treated carefully below −65° C. with 35ml HCl (37%). The mixture was washed with water and NaHCO₃ aq. and theorganic phase was dried with MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica eluting with ethyl acetate/hexane 1:9 twice toafford 3.8 g (41%) of the title compound as yellow oil. MS (m/e): 227.1(M+H, 100%).

Example N 3-Thioureido-benzenesulfonamide

A solution of 10 g (48 mmol) 3-Amino-benzenesulfonamide hydrochloride in100 ml THF and 8.2 ml (48 mmol) N,N-Diisopropylethylamine was treatedwith 6.45 ml (48 mmol) benzoyl isothiocyanate and allowed to stir atroom temperature. After evaporation to dryness the residue was suspendedin diethyl ether. The precipitate was filtered off, dried and suspendedin 130 ml methanol and 100 ml THF. K₂CO₃ (130 mmol) in 45 ml water wasadded and the mixture was stirred for 60 h at room temperature. Themixture was evaporated to drynes and the residue was treated with waterand extracted with ethyl acetate. The combined organic layers were driedwith MgSO₄ filtered and evaporated to dryness. After suspending theresidue in diethyl ether, filtration and drying 8.4 g (76%) of the titlecompound was obtained as white solid.

1-H-NMR (300 MHz-DMSO-d6): δ=10.0 (s, br, 2H, NH₂), 7.94 (d, J=1.7 Hz,1H, H-2), 7.71 (dd, J=7.7 Hz, J=1.7 Hz, 1H, H-4), 7.56 (m, 2H, H-5/H-6),7.36 (s, br, 2H, NH₂).

MS (m/e): 233.1 (M+H, 100%)

Example ON-Dimethylaminomethylene-3-(3-dimethylaminomethylene-thioureido)-benzenesulfonamide

A mixture of 2.3 g (9.9 mmol) 3-Thioureido-benzenesulfonamide and 17 mlN,N-Dimethylformamide dimethyl acetal was heated for 2 h to 90° C. Theprecipitate was filtered of washed with DCM/diethyl ether 1:3 and driedto yield 2.8 g (82%) of the title compound.

1-H-NMR (300 MHz-DMSO-d6): δ=10.7 (s, br, 2H, NH₂), 8.77 (s, 1H, CH),8.37 (s, br, 1H, CH), 8.17 (s, br, 1H, H-2), 7.58 (m, 1H, H-4), 7.40 (m,2H, H-5 /H-6).

MS (m/e): 340.2 (M+H, 100%)

Example P 3-(5-Benzoyl-thiazol-2-ylamino)-benzenesulfonamide

A mixture of 44 mg (0.13 mmol)N-Dimethylaminomethylene-3-(3-dimethylaminomethylene-thioureido)-benzenesulfonamideand 26 mg (0.13 mmol) phenacyl bromide in 0.8 ml DMF was stirred for 16h at room temperature. 0.12 ml HCl (37%) was added and the mixture wasstirred for 69 h at 100° C. After addition of 0.12 mlN,N-Diisopropylethylamine the mixture was subjected to preparative HPLCseparation on reversed phase eluting with an acetonitrile/watergradient. Evaporation of the product fractions yielded 6 mg (13%) of thetitle compound.

1-H-NMR (500 MHz-DMSO): δ=11.25 (s, br, 1H, NH), 8.25 (s, 1H, H-2), 7.90(s, 1H, thiazole H), 7.85 (m, 3H, Ph), 7.60 (m, 5H, Ph), 7.40 (s, br,2H, NH₂).

MS (m/e): 358 (M−H, 100%)

Example Q (Example 111 in Table)3-[4-Methyl-5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-benzonitrile

To a mixture of 801 mg (5 mmol) 3-cyanophenylthioisocyanate in 5 ml 1NNaOH at 0° C. was added 473 mg acetamidine hydrochloride in 10 ml THFand allowed to stir at 0° C. for 16 h. The mixture was extracted withethylacetate and the combined organic layers were dried with MgSO4 andevaporated to dryness. The residue was purified by flash columnchromatography on silica eluting with ethylacetate/cyclohexane 1:2 toyield 510 mg (47%) of1-(1-Amino-ethylidene)-3-(3-cyano-phenyl)-thiourea. (MS (m/e): 219.2(M+H, 100%). A mixture of 50 mg (0.23 mmol)1-(1-Amino-ethylidene)-3-(3-cyano-phenyl)-thiourea, 92 mg (0.345 mmol)2-Bromo-1-(2-trifluoromethyl-phenyl)-ethanone and 48 ul triethylamine in1 ml ethanol was stirred for 16 h at room temperature. The mixtures werediluted with methanol and directly subjected to preparative HPLCseparation on reversed phase eluting with an acetonitrile/watergradient. Evaporation of the product fractions yielded 10.4 mg (12%) ofthe title compound. (MS (m/e): 386.2 (M−H, 100%)

According to Example B further aminothiazole derivatives have beensynthesised from 1-dimethylaminomethylene-thioureas and α-bromoketones.The results are comprised in the following list embracing Example 1 toExample 97 and Example 112.

According to Example P further aminothiazole derivatives have beensynthesised from 1-dimethylaminomethylene-thioureas and α-bromoketones.The results are comprised in the following list embracing Example 98 toExample 110.

mass No. Synthesised from MW name found 1 1-Dimethylaminomethylene-355.4 3-[5-(Naphthalene-2- 354.2 3-(3-cyano-phenyl)-thioureacarbonyl)-thiazol-2- M − H and 2-Bromo-1-naphthalen-ylamino]-benzonitrile 2-yl-ethanone (commercially available) 21-Dimethylaminomethylene- 305.4 3-(5-Benzoyl-thiazol-2- 304.13-(3-cyano-phenyl)-thiourea ylamino)-benzonitrile M − H and phenacylbromide (commercially available) 3 1-Dimethylaminomethylene- 319.43-[5-(4-Methyl-benzoyl)- 318.2 3-(3-cyano-phenyl)-thioureathiazol-2-ylamino]- M − H and 2-Bromo-1-p-tolyl- benzonitrile ethanone(commercially available) 4 1-Dimethylaminomethylene- 358.4[2-(3-Methanesulfonyl- 357.1 3-(3-methanesulfonyl-phenylamino)-thiazol-5- M − H phenyl)-thiourea and yl]-phenyl-methanonephenacyl bromide (commercially available) 5 1-Dimethylaminomethylene-310.4 [2-(3-Methoxy- 309.1 3-(3-methoxy-phenyl)- phenylamino)-thiazol-5-M − H thiourea (US4532348) and yl]-phenyl-methanone phenacyl bromide(commercially available) 6 1-Dimethylaminomethylene- 348.3 Phenyl-[2-(3-349.3 3-(3-trifluoromethyl- trifluoromethyl- M + H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanonephenacyl bromide (commercially available) 7 1-Dimethylaminomethylene-335.4 3-[5-(3-Methoxy- 334.2 3-(3-cyano-phenyl)-thioureabenzoyl)-thiazol-2- M − H and 2-Bromo-1-(3-methoxy-ylamino]-benzonitrile phenyl)-ethanone (commercially available) 81-Dimethylaminomethylene- 323.4 3-[5-(4-Fluoro-benzoyl)- 322.23-(3-cyano-phenyl)-thiourea thiazol-2-ylamino]- M − H and2-Bromo-1-(4-fluoro- benzonitrile phenyl)-ethanone (commerciallyavailable) 9 1-Dimethylaminomethylene- 339.8 3-[5-(4-Chloro-benzoyl)-338.1 3-(3-cyano-phenyl)-thiourea thiazol-2-ylamino]- M − H and2-Bromo-1-(4-chloro- benzonitrile phenyl)-ethanone (commerciallyavailable) 10 1-Dimethylaminomethylene- 367.2 [2-(3,5-Dichloro- 365.03-(3,5-dichloro-phenyl)- phenylamino)-thiazol-5- M − H thiourea(commercially yl]-(2-fluoro-phenyl)- available) and 2-Bromo-1- methanone(2-fluoro-phenyl)-ethanone (commercially available) 111-Dimethylaminomethylene- 383.7 (2-Chloro-phenyl)-[2- 383.13-(3,5-dichloro-phenyl)- (3,5-dichloro- M − H thiourea (commerciallyphenylamino)-thiazol-5- available) and 2-Bromo-1- yl]-methanone(2-chloro-phenyl)-ethanone (commercially available) 121-Dimethylaminomethylene- 384.3 3-[5-(4-Bromo-benzoyl)- 384.13-(3-cyano-phenyl)-thiourea thiazol-2-ylamino]- M − H and2-Bromo-1-(4-bromo- benzonitrile phenyl)-ethanone (commerciallyavailable) 13 1-Dimethylaminomethylene- 339.8 3-[5-(3-Chloro-benzoyl)-338.1 3-(3-cyano-phenyl)-thiourea thiazol-2-ylamino]- M − H and2-Bromo-1-(3-chloro- benzonitrile phenyl)-ethanone (commerciallyavailable) 14 1-Dimethylaminomethylene- 323.4 3-[5-(2-Fluoro-benzoyl)-322.2 3-(3-cyano-phenyl)-thiourea thiazol-2-ylamino]- M − H and2-Bromo-1-(2-fluoro- benzonitrile phenyl)-ethanone (commerciallyavailable) 15 1-Dimethylaminomethylene- 323.4 3-[5-(3-Fluoro-benzoyl)-322.3 3-(3-cyano-phenyl)-thiourea thiazol-2-ylamino]- M − H and2-Bromo-1-(3-fluoro- benzonitrile phenyl)-ethanone (commerciallyavailable) 16 1-Dimethylaminomethylene- 335.4 3-[5-(2-Methoxy- 334.23-(3-cyano-phenyl)-thiourea benzoyl)-thiazol-2- M − H and2-Bromo-1-(2-methoxy- ylamino]-benzonitrile phenyl)-ethanone(commercially available) 17 1-Dimethylaminomethylene- 373.43-[5-(3-Trifluoromethyl- 372.2 3-(3-cyano-phenyl)-thioureabenzoyl)-thiazol-2- M − H and 2-Bromo-1-(3- ylamino]-benzonitriletrifluoromethyl-phenyl)- ethanone (WO0144201) 181-Dimethylaminomethylene- 339.8 3-[5-(2-Chloro-benzoyl)- 338.03-(3-cyano-phenyl)-thiourea thiazol-2-ylamino]- M − H and2-Bromo-1-(2-chloro-phenyl)- benzonitrile ethanone (commerciallyavailable) 19 1-Dimethylaminomethylene- 384.3 3-[5-(3-Bromo-benzoyl)-384.1 3-(3-cyano-phenyl)-thiourea thiazol-2-ylamino]- M − H and2-Bromo-1-(3-bromo- benzonitrile phenyl)-ethanone (commerciallyavailable) 20 1-Dimethylaminomethylene- 332.8 [2-(4-Chloro- 332.23-(4-chloro-phenyl)- phenylamino)-thiazol-5- M + H thiourea(commercially yl]-(2-fluoro-phenyl)- available) and 2-Bromo-1- methanone(2-fluoro-phenyl)-ethanone (commercially available) 211-Dimethylaminomethylene- 349.2 (2-Chloro-phenyl)-[2-(4- 349.23-(4-chloro-phenyl)- chloro-phenylamino)- M + H thiourea (commerciallythiazol-5-yl]-methanone available) and 2-Bromo-1-(4-chloro-phenyl)-ethanone (commercially available) 221-Dimethylaminomethylene- 362.4 p-Tolyl-[2-(3- 363.03-(3-trifluoromethyl- trifluoromethyl- M + H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(4-methyl- phenyl)-ethanone (commercially available) 231-Dimethylaminomethylene- 366.3 (4-Fluoro-phenyl)-[2-(3- 367.13-(3-trifluoromethyl- trifluoromethyl- M + H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(4-fluoro- phenyl)-ethanone (commercially available) 241-Dimethylaminomethylene- 378.4 (3-Methoxy-phenyl)-[2- 379.23-(3-trifluoromethyl- (3-trifluoromethyl- M + H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(3-methoxy- phenyl)-ethanone (commercially available) 251-Dimethylaminomethylene- 382.8 (3-Chloro-phenyl)-[2-(3- 383.23-(3-trifluoromethyl- trifluoromethyl- M + H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(3-chloro- phenyl)-ethanone (commercially available) 261-Dimethylaminomethylene- 366.3 (2-Fluoro-phenyl)-[2-(3- 367.13-(3-trifluoromethyl- trifluoromethyl- M + H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(2-fluoro- phenyl)-ethanone (commercially available) 271-Dimethylaminomethylene- 366.3 (3-Fluoro-phenyl)-[2-(3- 367.13-(3-trifluoromethyl- trifluoromethyl- M + H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(3-fluoro- phenyl)-ethanone (commercially available) 281-Dimethylaminomethylene- 378.4 (2-Methoxy-phenyl)-[2- 379.23-(3-trifluoromethyl- (3-trifluoromethyl- M + H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(2-methoxy- phenyl)-ethanone (commercially available) 291-Dimethylaminomethylene- 382.8 (2-Chloro-phenyl)-[2-(3- 383.13-(3-trifluoromethyl- trifluoromethyl- M + H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(2-chloro- phenyl)-ethanone (commercially available) 301-Dimethylaminomethylene- 427.2 (3-Bromo-phenyl)-[2-(3- 427.23-(3-trifluoromethyl- trifluoromethyl- M + H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(3-bromo- phenyl)-ethanone (commercially available) 311-Dimethylaminomethylene- 295.4 [2-(Pyridin-4-ylamino)- 296.23-pyridin-4-yl-thiourea and thiazol-5-yl]-o-tolyl- M + H2-Bromo-1-(2-methyl- methanone phenyl)-ethanone (WO9907666) 321-Dimethylaminomethylene- 350.2 (2,4-Dichloro-phenyl)-[2- 350.23-pyridin-4-yl-thiourea and (pyridin-4-ylamino)- M + H2-Bromo-1-(2,4-dichloro- thiazol-5-yl]-methanone phenyl)-ethanone(commercially available) 33 1-Dimethylaminomethylene- 309.4(2,4-Dimethyl-phenyl)-[2- 310.2 3-pyridin-4-yl-thiourea and(pyridin-4-ylamino)- M + H 2-Bromo-1-(2,4-dimethyl-thiazol-5-yl]-methanone phenyl)-ethanone (commercially available) 341-Dimethylaminomethylene- 326.3 (2-Nitro-phenyl)-[2- 327.23-pyridin-4-yl-thiourea and (pyridin-4-ylamino)- M + H2-Bromo-1-(2-nitro- thiazol-5-yl]-methanone phenyl)-ethanone(commercially available) 35 1-Dimethylaminomethylene- 306.33-[5-(Pyridine-2- 307.2 3-(3-cyano-phenyl)-thiourea carbonyl)-thiazol-2-M + H and 2-Bromo-1-pyridin-2-yl- ylamino]-benzonitrile ethanone(commercially available) 36 1-Dimethylaminomethylene- 306.33-[5-(Pyridine-3- 307.2 3-(3-cyano-phenyl)-thiourea carbonyl)-thiazol-2-M + H and 2-Bromo-1-pyridin-3-yl- ylamino]-benzonitrile ethanone(commercially available) 37 1-Dimethylaminomethylene- 306.33-[5-(Pyridine-4- 307.2 3-(3-cyano-phenyl)-thiourea carbonyl)-thiazol-2-M + H and 2-Bromo-1-pyridin-4-yl- ylamino]-benzonitrile ethanone(commercially available) 38 1-Dimethylaminomethylene- 319.43-[5-(2-Methyl-benzoyl)- 320.3 3-(3-cyano-phenyl)-thioureathiazol-2-ylamino]- M + H and 2-Bromo-1-(2-methyl- benzonitrilephenyl)-ethanone (WO9907666) 39 1-Dimethylaminomethylene- 311.4 3-(5-312.2 3-(3-cyano-phenyl)-thiourea Cyclohexanecarbonyl- M + H and2-Bromo-1- thiazol-2-ylamino)- (cyclohexyl)-ethanone benzonitrile(WO9940088) 40 1-Dimethylaminomethylene- 374.3 3-[5-(2,4-Dichloro- 374.23-(3-cyano-phenyl)-thiourea benzoyl)-thiazol-2- M + H and2-Bromo-1-(2,4- ylamino]-benzonitrile dichloro-phenyl)-ethanone(commercially available) 41 1-Dimethylaminomethylene- 333.43-[5-(2,4-Dimethyl- 334.2 3-(3-cyano-phenyl)-thioureabenzoyl)-thiazol-2- M + H and 2-Bromo-1-(2,4- ylamino]-benzonitriledimethyl-phenyl)-ethanone (commercially available) 421-Dimethylaminomethylene- 350.4 3-[5-(2-Nitro-benzoyl)- 351.33-(3-cyano-phenyl)-thiourea thiazol-2-ylamino]- M + H and2-Bromo-1-(2-nitro- benzonitrile phenyl)-ethanone (commerciallyavailable) 43 1-Dimethylaminomethylene- 328.4 (2-Fluoro-phenyl)-[2-(3-327.2 3-(3-metoxy-phenyl)- methoxy-phenylamino)- M − H thiourea(US4532348) and 2- thiazol-5-yl]-methanone Bromo-1-(2-fluoro-phenyl)-ethanone (commercially available) 44 1-Dimethylaminomethylene- 324.4[2-(3-Methoxy- 323.3 3-(3-metoxy-phenyl)- phenylamino)-thiazol-5- M − Hthiourea (US4532348) and 2- yl]-o-tolyl-methanone Bromo-1-(2-methyl-phenyl)-ethanone (WO9907666) 45 1-Dimethylaminomethylene- 338.4(2,4-Dimethyl-phenyl)-[2- 337.1 3-(3-metoxy-phenyl)- (3-methoxy- M − Hthiourea (US4532348) and 2- phenylamino)-thiazol-5-Bromo-1-(2,4-dimethyl- yl]-methanone phenyl)-ethanone (commerciallyavailable) 46 1-Dimethylaminomethylene- 355.4 [2-(3-Methoxy- 354.13-(3-metoxy-phenyl)- phenylamino)-thiazol-5- M − H thiourea (US4532348)and 2- yl]-(2-nitro-phenyl)- Bromo-1-(2-nitro-phenyl)- methanoneethanone (commercially available) 47 1-Dimethylaminomethylene- 349.3Pyridin-4-yl-[2-(3- 348.2 3-(3-trifluoromethyl- trifluoromethyl- M − Hphenyl)-thiourea phenylamino)-thiazol-5- (commercially available) andyl]-methanone 2-Bromo-1-pyridin-4-yl- ethanone (commercially available)48 1-Dimethylaminomethylene- 362.4 o-Tolyl-[2-(3- 361.13-(3-trifluoromethyl- trifluoromethyl- M − H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(2-methyl- phenyl)-ethanone (commercially available) 491-Dimethylaminomethylene- 354.4 Cyclohexyl-[2-(3- 353.23-(3-trifluoromethyl- trifluoromethyl- M − H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(cyclohexyl)- ethanone (WO9940088) 501-Dimethylaminomethylene- 417.2 (2,4-Dichloro-phenyl)-[2- 417.23-(3-trifluoromethyl- (3-trifluoromethyl- M − H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(2,4-dichloro- phenyl)-ethanone (commercially available) 511-Dimethylaminomethylene- 376.4 (2,4-Dimethyl-phenyl)-[2- 375.33-(3-trifluoromethyl- (3-trifluoromethyl- M − H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(2,4-methyl- phenyl)-ethanone (commercially available) 521-Dimethylaminomethylene- 393.3 (2-Nitro-phenyl)-[2-(3- 392.13-(3-trifluoromethyl- trifluoromethyl- M − H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(2-nitro- phenyl)-ethanone (commercially available) 531-Dimethylaminomethylene- 316.3 (2-Fluoro-phenyl)-[2-(3- 317.23-(3-fluoro-phenyl)-thiourea fluoro-phenylamino)- M + H (commerciallyavailable) and thiazol-5-yl]-methanone 2-Bromo-1-(2-fluoro-phenyl)-ethanone (commercially available) 54 1-Dimethylaminomethylene-312.4 [2-(3-Fluoro- 313.2 3-(3-fluoro-phenyl)-thioureaphenylamino)-thiazol-5- M + H (commercially available) andyl]-o-tolyl-methanone 2-Bromo-1-(2-methyl- phenyl)-ethanone (WO9907666)55 1-Dimethylaminomethylene- 332.8 (2-Chloro-phenyl)-[2-(3- 333.23-(3-fluoro-phenyl)-thiourea fluoro-phenylamino)- M + H (commerciallyavailable) and thiazol-5-yl]-methanone 2-Bromo-1-(2-chloro-phenyl)-ethanone (commercially available) 56 1-Dimethylaminomethylene-359.2 [2-(3-Bromo- 361.1 3-(3-bromo-phenyl)- phenylamino)-thiazol-5- M +H thiourea and phenacyl yl]-phenyl-methanone bromide (commerciallyavailable) 57 1-Dimethylaminomethylene- 373.3 [2-(3-Bromo- 373.03-(3-bromo-phenyl)- phenylamino)-thiazol-5- M + H thiourea and2-Bromo-1-(2- yl]-o-tolyl-methanone methyl-phenyl)-ethanone (WO9907666)58 1-Dimethylaminomethylene- 393.7 [2-(3-Bromo- 393.43-(3-bromo-phenyl)- phenylamino)-thiazol-5- M + H thiourea and2-Bromo-1-(2- yl]-(2-chloro-phenyl)- chloro-phenyl)-ethanone methanone(commercially available) 59 1-Dimethylaminomethylene- 387.3 [2-(3-Bromo-387.2 3-(3-bromo-phenyl)- phenylamino)-thiazol-5- M + H thiourea and2-Bromo-1- yl]-(2,4-dimethyl-phenyl)- (2,4-dimethyl-phenyl)- methanoneethanone (commercially available) 60 1-Dimethylaminomethylene- 340.41-{3-[5-(2-Fluoro- 341.2 3-(3-acetyl-phenyl)-thioureabenzoyl)-thiazol-2- M + H and 2-Bromo-1-(2-fluoro- ylamino]-phenyl}-phenyl)-ethanone ethanone (commercially available) 611-Dimethylaminomethylene- 336.4 1-{3-[5-(2-Methyl- 337.23-(3-acetyl-phenyl)-thiourea benzoyl)-thiazol-2- M + H and2-Bromo-1-(2-methyl- ylamino]-phenyl}- phenyl)-ethanone ethanone(WO9907666) 62 1-Dimethylaminomethylene- 356.8 1-{3-[5-(2-Chloro- 357.23-(3-acetyl-phenyl)-thiourea benzoyl)-thiazol-2- M + H and2-Bromo-1-(2-fluoro- ylamino]-phenyl}- phenyl)-ethanone ethanone(commercially available) 63 1-Dimethylaminomethylene- 350.41-{3-[5-(2,4-Dimethyl- 351.3 3-(3-acetyl-phenyl)-thioureabenzoyl)-thiazol-2- M + H and 2-Bromo-1-(2,4- ylamino]-phenyl}-dimethyl-phenyl)-ethanone ethanone (commercially available) 641-Dimethylaminomethylene- 299.3 (2-Fluoro-phenyl)-[2- 300.43-pyridin-3-yl-thiourea and (pyridin-3-ylamino)- M + H2-Bromo-1-(2-fluoro- thiazol-5-yl]-methanone phenyl)-ethanone(commercially available) 65 1-Dimethylaminomethylene- 295.4[2-(Pyridin-3-ylamino)- 296.3 3-pyridin-3-yl-thiourea andthiazol-5-yl]-o-tolyl- M + H 2-Bromo-1-(2-methyl- methanonephenyl)-ethanone (WO9907666) 66 1-Dimethylaminomethylene- 315.8(2-Chloro-phenyl)-[2- 316.2 3-pyridin-3-yl-thiourea and(pyridin-3-ylamino)- M + H 2-Bromo-1-(2-chloro- thiazol-5-yl]-methanonephenyl)-ethanone (commercially available) 67 1-Dimethylaminomethylene-321.4 3-[5-(3-Methyl-pyrazine- 320.2 3-(3-cyano-phenyl)-thiourea2-carbonyl)-thiazol-2- M − H and 2-Bromo-1-(3-methyl-ylamino]-benzonitrile pyrazin-2-yl)-ethanone dihydrobromide 681-Dimethylaminomethylene- 335.4 3-[5-(3-Ethyl-pyrazine-2- 334.23-(3-cyano-phenyl)-thiourea carbonyl)-thiazol-2- M − H and2-Bromo-1-(3-methyl- ylamino]-benzonitrile pyrazin-2-yl)-ethanonedihydrobromide 69 1-Dimethylaminomethylene- 325.4 3-[5-(3-Methyl- 324.23-(3-cyano-phenyl)-thiourea thiophene-2-carbonyl)- M − H and2-Bromo-1-(3-methyl- thiazol-2-ylamino]- thiophen-2-yl)-ethanonebenzonitrile (EO432040) 70 1-Dimethylaminomethylene- 333.43-[5-(2-Ethyl-benzoyl)- 332.2 3-(3-cyano-phenyl)-thioureathiazol-2-ylamino]- M − H and 2-Bromo-1-(2-ethyl- benzonitrilephenyl)-ethanone 71 1-Dimethylaminomethylene- 373.43-[5-(2-Trifluoromethyl- 372.2 3-(3-cyano-phenyl)-thioureabenzoyl)-thiazol-2- M − H and 2-Bromo-1-(2- ylamino]-benzonitriletrifluoromethyl-phenyl)- ethanone (EP432040) 721-Dimethylaminomethylene- 320.4 3-[5-(3-Methyl-pyridine- 319.13-(3-cyano-phenyl)-thiourea 2-carbonyl)-thiazol-2- M − H and2-Bromo-1-(3-methyl- ylamino]-benzonitrile pyridin-2-yl)-ethanone(WO9935130) 73 1-Dimethylaminomethylene- 320.4 3-[5-(2-Methyl-pyridine-319.2 3-(3-cyano-phenyl)-thiourea 3-carbonyl)-thiazol-2- M − H and2-Bromo-1-(2-methyl- ylamino]-benzonitrile pyridin-3-yl)-ethanone (J.Heterocycl. Chem. 1978, 15, 217) 74 1-Dimethylaminomethylene- 339.43-[5-(2,5-Dimethyl- 338.1 3-(3-cyano-phenyl)-thioureathiophene-3-carbonyl)- M − H and 2-Bromo-1-(2,5- thiazol-2-ylamino]-dimethyl-thiophen-3-yl)- benzonitrile ethanone (WO9921845) 751-Dimethylaminomethylene- 368.4 (3-Methyl-thiophen-2-yl)- 367.13-(3-trifluoromethyl- [2-(3-trifluoromethyl- M − H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(3-methyl- thiophen-2-yl)-ethanone (EO432040) 761-Dimethylaminomethylene- 376.4 (2-Ethyl-phenyl)-[2-(3- 375.33-(3-trifluoromethyl- trifluoromethyl- M − H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(2-ethyl- phenyl)-ethanone 77 1-Dimethylaminomethylene- 416.3(2-Trifluoromethyl- 415.2 3-(3-trifluoromethyl- phenyl)-[2-(3- M − Hphenyl)-thiourea trifluoromethyl- (commercially available) andphenylamino)-thiazol-5- 2-Bromo-1-(2- yl]-methanonetrifluoromethyl-phenyl)- ethanone (EP432040) 781-Dimethylaminomethylene- 363.4 (3-Methyl-pyridin-2-yl)- 362.13-(3-trifluoromethyl- [2-(3-trifluoromethyl- M − H phenyl)-thioureaphenylamino)-thiazol-5- (commercially available) and yl]-methanone2-Bromo-1-(3-methyl- pyridin-2-yl)-ethanone (WO9935130) 791-Dimethylaminomethylene- 382.4 (2,5-Dimethyl-thiophen- 381.23-(3-trifluoromethyl- 3-yl)-[2-(3- M − H phenyl)-thioureatrifluoromethyl- (commercially available) and phenylamino)-thiazol-5-2-Bromo-1-(2,5-dimethyl- yl]-methanone thiophen-3-yl)-ethanone(WO9921845) 80 1-Dimethylaminomethylene- 308.4 o-Tolyl-(2-m-tolylamino-307.2 3-(3-methyl-phenyl)- thiazol-5-yl)-methanone M − H thiourea and2-Bromo-1-(2- methyl-phenyl)-ethanone (WO9907666) 811-Dimethylaminomethylene- 322.4 (2-Ethyl-phenyl)-(2-m- 321.23-(3-methyl-phenyl)- tolylamino-thiazol-5-yl)- M − H thiourea and2-Bromo-1-(2- methanone ethyl-phenyl)-ethanone 821-Dimethylaminomethylene- 362.4 (2-m-Tolylamino-thiazol- 361.03-(3-methyl-phenyl)- 5-yl)-(2-trifluoromethyl- M − H thiourea and2-Bromo-1-(2- phenyl)-methanone trifluoromethyl-phenyl)- ethanone(EP432040) 83 1-Dimethylaminomethylene- 312.4 (2-Fluoro-phenyl)-(2-m-311.1 3-(3-methyl-phenyl)- tolylamino-thiazol-5-yl)- M − H thiourea and2-Bromo-1-(2- methanone fluoro-phenyl)-ethanone (commercially available)84 1-Dimethylaminomethylene- 328.8 (2-Chloro-phenyl)-(2-m- 327.13-(3-methyl-phenyl)- tolylamino-thiazol-5-yl)- M − H thiourea and2-Bromo-1-(2- methanone chloro-phenyl)-ethanone (commercially available)85 1-Dimethylaminomethylene- 324.4 (2-Methoxy-phenyl)-(2- 323.23-(3-methyl-phenyl)- m-tolylamino-thiazol-5- M − H thiourea and2-Bromo-1-(2- yl)-methanone methoxy-phenyl)-ethanone (commerciallyavailable) 86 1-Dimethylaminomethylene- 328.5 (2,5-Dimethyl-thiophen-327.2 3-(3-methyl-phenyl)- 3-yl)-(2-m-tolylamino- M − H thiourea and2-Bromo-1- thiazol-5-yl)-methanone (2,5-dimethyl-thiophen-3-yl)-ethanone (WO9921845) 87 1-Dimethylaminomethylene- 372.5[2-(3-Methanesulfonyl- 371.1 3-(3-methanesulfonyl-phenylamino)-thiazol-5- M − H phenyl)-thiourea and 2-yl]-o-tolyl-methanone Bromo-1-(2-methyl-phenyl)- ethanone (WO9907666) 881-Dimethylaminomethylene- 386.5 (2-Ethyl-phenyl)-[2-(3- 385.13-(3-methanesulfonyl- methanesulfonyl- M − H phenyl)-thiourea and 2-phenylamino)-thiazol-5- Bromo-1-(2-ethyl-phenyl)- yl]-methanone ethanone89 1-Dimethylaminomethylene- 426.4 [2-(3-Methanesulfonyl- 425.23-(3-methanesulfonyl- phenylamino)-thiazol-5- M − H phenyl)-thiourea and2- yl]-(2-trifluoromethyl- Bromo-1-(2-trifluoromethyl- phenyl)-methanonephenyl)-ethanone (EP432040) 90 1-Dimethylaminomethylene- 392.9(2-Chloro-phenyl)-[2-(3- 391.0 3-(3-methanesulfonyl- methanesulfonyl- M− H phenyl)-thiourea and 2- phenylamino)-thiazol-5-Bromo-1-(2-chloro-phenyl)- yl]-methanone ethanone (commerciallyavailable) 91 1-Dimethylaminomethylene- 373.5 [2-(3-Methanesulfonyl-372.1 3-(3-methanesulfonyl- phenylamino)-thiazol-5- M − Hphenyl)-thiourea and 2- yl]-(4-methyl-pyridin-3-Bromo-1-(4-methyl-pyridin- yl)-methanone 3-yl)-ethanone 921-Dimethylaminomethylene- 392.5 (2,5-Dimethyl-thiophen- 391.03-(3-methanesulfonyl- 3-yl)-[2-(3- M − H phenyl)-thiourea and 2-methanesulfonyl- Bromo-1-(2,5-dimethyl- phenylamino)-thiazol-5-thiophen-3-yl)-ethanone yl]-methanone (WO9921845) 931-(2-Cyano-pyridin-4-yl)-3- 334.4 4-[5-(2-Ethyl-benzoyl)- 333.1dimethylaminomethylene- thiazol-2-ylamino]- M − H thiourea and2-Bromo-1-(2- pyridine-2-carbonitrile ethyl-phenyl)-ethanone 941-(2-Cyano-pyridin-4-yl)-3- 321.4 4-[5-(3-Methyl-pyridine- 320.2dimethylaminomethylene- 2-carbonyl)-thiazol-2- M − H thiourea and2-Bromo-1-(3- ylamino]-pyridine-2- methyl-pyridin-2-yl)- carbonitrileethanone (WO9935130) 95 1-(2-Cyano-pyridin-4-yl)-3- 320.44-[5-(2-Methyl-benzoyl)- 319.1 dimethylaminomethylene-thiazol-2-ylamino]- M − H thiourea and 2-Bromo-1-(2-pyridine-2-carbonitrile methyl-phenyl)-ethanone (WO9907666) 961-(2-Cyano-pyridin-4-yl)-3- 340.8 4-[5-(2-Chloro-benzoyl)- 339.0dimethylaminomethylene- thiazol-2-ylamino]- M − H thiourea and2-Bromo-1-(2- pyridine-2-carbonitrile chloro-phenyl)-ethanone(commercially available) 97 1-(2-Cyano-pyridin-4-yl)-3- 324.34-[5-(2-Fluoro-benzoyl)- 323.3 dimethylaminomethylene-thiazol-2-ylamino]- M − H thiourea and 2-Bromo-1-(2-pyridine-2-carbonitrile fluoro-phenyl)-ethanone (commercially available)98 N- 373.5 3-[5-(2-Methyl-benzoyl)- 372.1 Dimethylaminomethylene-3-thiazol-2-ylamino]- M − H (3- benzenesulfonamide dimethylaminomethylene-thioureido)- benzenesulfonamide and 2- Bromo-1-(2-methyl-phenyl)-ethanone (WO9907666) 99 N- 387.5 3-[5-(2-Ethyl-benzoyl)- 386.1Dimethylaminomethylene-3- thiazol-2-ylamino]- M − H (3-benzenesulfonamide dimethylaminomethylene- thioureido)-benzenesulfonamide and 2- Bromo-1-(2-ethyl-phenyl)- ethanone 100 N-389.5 3-[5-(4-Hydroxy-2- 388.1 Dimethylaminomethylene-3-methyl-benzoyl)-thiazol- M − H (3- 2-ylamino]- dimethylaminomethylene-benzenesulfonamide thioureido)- benzenesulfonamide and 2-Bromo-1-(4-hydroxy-2- methyl-phenyl)-ethanone (EP1104760) 101 N- 427.43-[5-(2-Trifluoromethyl- 427.4 Dimethylaminomethylene-3-benzoyl)-thiazol-2- M − H (3- ylamino]- dimethylaminomethylene-benzenesulfonamide thioureido)- benzenesulfonamide and 2-Bromo-1-(2-trifluoromethyl- phenyl)-ethanone (EP432040) 102 N- 377.43-[5-(2-Fluoro-benzoyl)- 376.2 Dimethylaminomethylene-3-thiazol-2-ylamino]- M − H (3- benzenesulfonamide dimethylaminomethylene-thioureido)- benzenesulfonamide and 2- Bromo-1-(2-fluoro-phenyl)-ethanone (commercially available) 103 N- 393.9 3-[5-(2-Chloro-benzoyl)-392.0 Dimethylaminomethylene-3- thiazol-2-ylamino]- M − H (3-benzenesulfonamide dimethylaminomethylene- thioureido)-benzenesulfonamide and 2- Bromo-1-(2-chloro-phenyl)- ethanone(commercially available) 104 N- 389.5 3-[5-(2-Methoxy- 388.1Dimethylaminomethylene-3- benzoyl)-thiazol-2- M − H (3- ylamino]-dimethylaminomethylene- benzenesulfonamide thioureido)-benzenesulfonamide and 2- Bromo-1-(2-methoxy- phenyl)-ethanone(commercially available) 105 N- 377.4 3-[5-(3-Fluoro-benzoyl)- 376.2Dimethylaminomethylene-3- thiazol-2-ylamino]- M − H (3-benzenesulfonamide dimethylaminomethylene- thioureido)-benzenesulfonamide and 2- Bromo-1-(3-fluoro-phenyl)- ethanone(commercially available) 106 N- 393.9 3-[5-(3-Chloro-benzoyl)- 392.0Dimethylaminomethylene-3- thiazol-2-ylamino]- M − H (3-benzenesulfonamide dimethylaminomethylene- thioureido)-benzenesulfonamide and 2- Bromo-1-(3-chloro-phenyl)- ethanone(commercially available) 107 N- 374.4 3-[5-(4-Methyl-pyridine- 373.1Dimethylaminomethylene-3- 3-carbonyl)-thiazol-2- M − H (3- ylamino]-dimethylaminomethylene- benzenesulfonamide thioureido)-benzenesulfonamide and 2- Bromo-1-(4-methyl-pyridin- 3-yl)-ethanone 108N- 374.4 3-[5-(3-Methyl-pyridine- 373.1 Dimethylaminomethylene-3-2-carbonyl)-thiazol-2- M − H (3- ylamino]- dimethylaminomethylene-benzenesulfonamide thioureido)- benzenesulfonamide and 2-Bromo-1-(3-methyl-pyridin- 2-yl)-ethanone 109 N- 389.53-[5-(3-Ethyl-pyrazine-2- 387.8 Dimethylaminomethylene-3-carbonyl)-thiazol-2- M − H (3- ylamino]- dimethylaminomethylene-benzenesulfonamide thioureido)- benzenesulfonamide and 2-Bromo-1-(3-ethyl-pyrazin-2- yl)-ethanone dihydrobromide 110 N- 379.53-[5-(3-Methyl- 378.1 Dimethylaminomethylene-3- thiophene-2-carbonyl)- M− H (3- thiazol-2-ylamino]- dimethylaminomethylene- benzenesulfonamidethioureido)- benzenesulfonamide and 2- Bromo-1-(3-methyl-thiophen-2-yl)-ethanone (EO432040) 111 (see Example Q) 3-[4-Methyl-5-(2-trifluoromethyl-benzoyl)- thiazol-2-ylamino]- benzonitrile 1121-Dimethylaminomethylene- Phenyl-(2-m-tolylamino- 293.23-(3-methyl-phenyl)- thiazol-5-yl)-methanone M − H thiourea andphenacylbromide (commercially available)

Example A

A compound of formula I can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition:

Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mgCorn starch  25 mg Talc  25 mg Hydroxypropylmethylcellulose  20 mg 425mg

Example B

A compound of formula I can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition:

Per capsule Active ingredient 100.0 mg Corn starch  20.0 mg Lactose 95.0 mg Talc  4.5 mg Magnesium stearate  0.5 mg 220.0 mg

1. A compound of formula I:

wherein: R¹ is aryl or heteroaryl, wherein at least one of the two metapositions of each aryl and heteroaryl group is substituted with R⁵; R²is hydrogen, alkyl or cycloalkyl; R³ is cycloalkyl or aryl, wherein atleast one of the two ortho positions of each cycloalkyl or aryl group issubstituted with R⁶; R⁴ is hydrogen, alkyl or cycloalkyl; R⁵ is cyano,trifluoromethyl, alkyl-SO₂—, amino-SO₂—, or alkylcarbonyl; and R⁶ ishydrogen, halogen, cyano, nitro, trifluoromethyl, alkyl, alkoxy, hydroxyor alkoxycarbonyl; or a pharmaceutically acceptable salt or esterthereof.
 2. The compound according to claim 1, wherein R⁵ is selectedfrom cyano, trifluoromethyl, methyl-SO₂—, NH₂—SO₂— and methylcarbonyl.3. The compound according to claim 1 selected from3-[5-(2-Fluoro-benzoyl)-thiazol-2-ylamino]-benzonitrile;3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-benzonitrile;(2-Chloro-phenyl)-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;o-Tolyl-[2-(3-trifluoromethyl-phenylamino)-thiazol-5-yl]-methanone;1-{3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-ethanone;3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;3-[5-(2-Trifluoromethyl-benzoyl)-thiazol-2-ylamino]-benzonitrile;[2-(3-Methanesulfonyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone;(2-Ethyl-phenyl)-[2-(3-methanesulfonyl-phenylamino)-thiazol-5-yl]-methanone;4-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-pyridine-2-carbonitrile;4-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-pyridine-2-carbonitrile;3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide; and3-[5-(2-Trifluoromethyl-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide.4. A method for the treatment of obesity in a patient in need of saidtreatment, which comprises administering to said patient an effectiveamount of a compound of claim
 1. 5. The method according to claim 4,wherein said compound is administered orally in an amount of from about0.1 mg to 20 mg per kg per day.
 6. A pharmaceutical composition,comprising a therapeutically effective amount of a compound according toclaim 1, a therapeutically inert carrier and a therapeutically effectiveamount of orlistat.